Field of the Invention
The present invention relates generally to the fields of medicine and pharmaceuticals. In particular, multivalent integrin receptor antagonists are provided, including near-infrared (NIR), fluorescent, non-peptidic, integrin αvβ3 compounds (as well as formulations and compositions thereof) that are useful in a variety of prophylactic and/or therapeutic regimens, and one or more diagnostic imaging modalities, including, for example, in the detection of mammalian cancer cells in vivo, or in situ.
Description of Related Art
The integrins are a family of heterodimeric trans-membrane receptors each consisting of α and β subunits. To date, a total of 18 α and 8 β subunits have been discovered in mammalian cells, forming at least 24 different integrin receptors. Each integrin subunit includes a large extracellular, a single transmembrane and a short cytoplasmic domain. Based on the key roles they play in angiogenesis, leukocyte function and tumor development and their easy accessibility as cell surface receptors interacting with extracellular ligands, the integrin superfamily, integrin αvβ3 in particular, have been extensively investigated as imaging and chemotherapy targets (Chen, 2011).
Integrin αvβ3 is a receptor for extracellular proteins including vitronectin, fibronectin and fibrinogen that contain an arginine-glycine-aspartic acid (RGD) sequence (DeNardo et al., 2000; Janssen et al., 2004). RGD peptides specific binding to αvβ3 receptor have been labeled with various gamma and positron emitters for scintigraphic detection (Chen et al., 2004; Harris et al., 2003; Haubner et al., 2004; Haubner et al., 1999; van Hagen et al., 2000) and gamma and beta emitters for radiotherapy of tumors (Bernard et al., 2004; Capello et al., 2004; DeNardo et al., 2000; Janssen et al., 2004; Onthank et al., 2004). Steady progress has been reported in optimizing the labeling methodologies to increase tumor-to-nontumor tissue ratios, especially the tumor-to-liver and tumor-to-kidney ratios by increasing the hydrophilicity of the product via glycosylation and PEGylation of radiolabeled RGD peptides (Chen et al., 2004a; Chen et al., 2004b; Chen et al., 2004; Haubner et al., 2001). Dimeric and tetrameric RDG peptides labeled with 18F and 64Cu were prepared for positron emission tomography (PET) imaging for cancer diagnosis (Chen et al., 2004b; Chen et al., 2005; Wu et al., 2005). It was reported that these oligomeric RDG peptides enhanced the receptor-binding affinity, thereby improving the tumor targeting and slowing the wash-out of radioactivity from tumor.
Receptors on the surfaces of mammalian cells participate in many biological cellular processes, including, for example, cell proliferation and invasion. One particular receptor that has implications for a wide variety of disease conditions is the vitronectin receptor αvβ3. A member of the integrin superfamily of receptors, αvβ3 is found in various cells including angiogenic endothelia and osteoclasts. Integrins have been implicated in a variety of disorders and diseases and disorders, including, cancer and inflammation, as well as autoimmune and genetic diseases and disorders. αvβ3 plays a critical in vivo role in endothelial cell survival during angiogenesis, and also potentiates the internalization of various cellular viruses including, rotavirus, adenovirus, and foot-and-mouth disease virus.
Development of antagonists of the integrin αvβ3 receptor have been described, and monovalent integrin αvβ3 receptor antagonists having a tetrahydropyridi-midinylaminoethyloxybenzoyl group conjugated to a sulfonylamino-β-alanine nucleus have been synthesized as noted in U.S. Pat. Appl. Publ. No. 2006/0030575 (specifically incorporated herein in its entirety by express reference thereto). The development of multivalent integrin αvβ3 antagonists, have not, however, been reported.
Thus, there is a need in the art to develop new, improved integrin antagonist compounds that (1) bind to αvβ3 integrin receptors with higher specificity and/or higher affinity than existing compounds; (2) bind to selected target cells (such as, for example, mammalian tumor cells) with high affinity, and with substantial specificity; and (3) are more resistant to cleavage and/or degradation from one or more endogenous or exogenous proteases (including, for example, those found in plasma, the gastrointestinal tract, tumor cells, and other mammalian tissues).